Method for making hydrogenation products of ketones of the pyridine and piperidine series



Patented Nov. 13, 1934 UNITED STATES METHOD FOR MAKING HYDROGENATION PRODUCTS OF KETONES OF THE PYRI- DINE AND PIPERIDINE SERIES Georg Scheuing and Ludwig Winterhalder,

Nieder-Ingelheim-on-the-Rhine, Germany, assignors to firm of C. H. Boehringer Sohn, Nieder-Ingelheim-on-the-Rhine, Germany, a

society of Germany No Drawing. Application June 1, 1929, Serial No. 367,827. In Germany June 1, 1928 35 Claims.

This invention relates to a method for making hydrogenation-products of ketones of the pyridine and piperidine series.

We have found that hydrogenation of compounds of the pyridine or piperidine series containing in ocor ocand a position side chains with ketonic groups, especially hydrogenation of phenacyl compounds of the pyridine or piperidine series furnishes products which either themselves are therapeutically valuable or may be used as intermediate products for the manufacture of therapeutically valuable products.

The starting materials may have in aor ocand oU-position one or more side chains such as com- 0 pounds of the type --CH2-COR, in which R is a carbocyclic radical, preferably a phenyl radical. On two side chains there may be two different carbocyclic radicals R and R1 in the starting material. The N-atom of the starting materials used for the hydrogenation may be combined with an hydrogenatom or any desired radical such as an alkyl or aralkl group. Furthermore the starting materials may have a substituent of any kind such as hydrocarbon radicals, amino groups, halogen or the like in the pyridine or piperidine nucleus, in one of the carbocyclic groups R and R1 present and respectively or in the substituent combined with the N-atom. The hydrogenation of the starting materials as well in the pyridine nucleus as in one or both of the keto groups may be carried out'continuously, intermittently or simultaneously. Also polycyclic compounds derived from ketones of the pyridine or piperidine series such as wholly or partially 0 hydrogenated or not hydrogenated ketones of the quinoline series, having for example the group CI-lzCO-R in ix-position to the N-atom, which may be combined with a hydrogen and may be used as starting material for the hydrogenation according to the invention.

The hydrogenation of the starting materials is carried out with gaseous hydrogen in presence of hydrogenation catalysts such asmetals of the platinum group for example platinum, palladium and the like or their compounds or oxides such as platinum oxide. Also other metals or metal compounds such as nickel and the like may be used as catalysts alone or in mixture with the above mentioned catalysts. The catalysts may have any desired form and also be precipitated on carriers. For example platinum black, if necessary on one of the usual carriers, may be used. The hydrogenation may be carried out at atmospheric or higher pressure.

The nature of the starting materials, which tion. Also by combination of several of these,

working conditions special effects may be obtained.

Thus for example a-phenacylpyridine of the formula m lronroo-oim may be converted into the corresponding pyridyl reduction product of the formula CEF CHIO H-CQH5 by shaking a solution of the free u-phenacylpyridine in methyl; alcohol and in presence of platinum oxide with hydrogen, the reaction terminating, when 1 mol hydrogen has been taken up. 7

If the same substance dissolved in glacial acetic acid is hydrogenated under the same working conditions, it is possible to combine the starting material with 4 mols of hydrogen, thereby obtaining a pyridyl reduction compound of the formula If two side chains with keto groups are present in the starting material, the reaction may for example be conducted in such a manner, that the CO-group in one side chain is converted into a secondary alcohol group, whereas the CO-group in the other side chain remains unchanged. q

This result may alsobe obtained by starting the hydrogenation at room temperature or in the cold, thus bringing the reaction to a standstill, when 3 mols of hydrogen are taken up, and completing the hydrogenation by heating thus reacting also the other CO-group, which remained unchanged during the first step. I

The hydrogenation may be carried out continuously or in stages. It is possible to isolate the products obtained in one or all of the different stages, which products may be purified and then subjected to a further hydrogenation treatment. This is however not necessary, as the reaction may also be completed without isolation of the intermediate products but with changes in the working conditions, in which case it is possible to obtain higher yields than without changes in the working conditions.

Also the sequence of the hydrogenation stages may vary in accordance with the nature of the starting materials. Thus for example, when hydrogenating pyridine compounds phenacylated in aand lad-position with the N-atom not carrying a substituent, hydrogenation of the carbonyl groups takes place before the hydrogenation of the pyridine nucleus, whereas with quaternary pyridinesalts hydrogenation of thenucleus takes place before hydrogenation of one or both of the carboxylic groups. Thus for example hydrogenation of cc' and a'-phenacy1ated derivatives of piperidine leads to compounds of the piperidine series, which contain in one or both side chains J' an hydroxy group for the oxygen of the carbonyl group.

Hydrogenation of quaternary pyridinium compounds leads according to the invention in a very easy manner to N-alkylated or N-aralkylated derivatives of the piperidine series, thus avoiding the difficult N-alkylation of piperidine derivatives with the usual alkylating means.

Thefollowing formulas may serve to illustrate the great importance and we wide rangeof the invention, showing how it is possible to make hydrogenation products from ketones directly or indirectly over isolated or nonis olated intermediate products (alcohols), which latter may also be obtained in a different manner.

l H N CHz-OQCgH5 CHr-CHOH-CQH5 2H5 (52115 Hz l i Hr Hz Hz- H:

H H H H H on 1% gN/gn I 2 I 2 $113. (113 A O O O HOH The possibility of obtaining diiferent hydro genation products from the same starting material may be illustrated by the following'examples:

Starting material Working conditions Products or phenylhydroxy cth-ylpyridine (1 mol' hydrogen Base dissolved in me.- thyl alcohol withplatinum oxide a-phenacylpyridine taken up) Do Hydrochloride dis- Do.

solved in alcohol with palladium on barium sulfate. Do.- Hydrochloride, disa phenlyhydroxy solved in alcohol ethylpiperidine, (4

with platinum oxide mols hydrogen takcn'up). Do Hydrochloride in gla- Do.

- -cial acetic acid with platinumoxide,until 4 mols hydrogen are I taken up. 11,01 diphenacyl- Base in methyl alcohol a,a' diphenylhypyridine. V with platinum oxide d roxyethylpyrlor hydrochloride in dine.v

alcohol with palladium on barium sulfate. I Do Hydrochlorideinalco 01,0! diphenylhyhol with platinum droxyetlhylpiperoxide or in glacial idine (nor:-lobelacetic acid with platanidine) inum oxide, until 5 mols hydrogen are taken up. I

Examples (1') 10 g. of u-phenacylpyridine are dissolved in 100'ccm. of glacial acetic acid and shaken with hydrogen in presence of platinum oxide. When i mols hydrogen are taken up nearly quantitative yields of phenyl-hydroxyethylpiperidine may be isolated from the glacial acetic acidsolution. l

The reaction is as follows:

(2) 31.5 g. 01 a,a'-diphenacylpyridine are dissolved in 500 com. of methyl alcohol, to which 25 com. of concentrated hydrochloric acid are added. The solution is shaken with hydrogen and palladium precipitated upon barium sulfate. When working at about 40 C. 2 mols of hydrogen are taken up after six hours, the adsorption of hydrogen then coming to a standstill. After removal of the catalyst and evaporation of the solvent 31 g. of a chlorhydrate melting at 222 C. are obtained. This chlorhydrate is the hydrochloride of a dialcohol corresponding to the starting material. I

The reaction is as follows:

HI\H H (3) 17.8 g. of 0 m-diphenylhydroxyethylpyridine chlorhydrate obtained according to example 2 are dissolved in 300 com. of methyl alcohol and shaken with 0.6 g. of platinum oxide and hydrogen at 40-50 C. 3.7 l of hydrogen are spent in about 8-9 hours and the velocity of hydrogenation then falls to about one fifteenth of the original velocity. When working up the reaction mixture two different chlorhydrates are obtained, of which one is very difiicultly soluble in alcohol, being chlorhydrate of the Nor-j Lobelanidine melting at 244 0., whereas the soluble chlorhydrate, melting at 200 C., is the hydrochloride of an isomeric compound of the Nor-Lobelanidine. Both bases, which are obtained in equal parts with a yield of about furnish Nor-Lobelanine on oxidation.

The reaction is as follows:

(4) 30 g. of the chlorhydrate of Nor-Lobelanine (c -diphenacylpiperidine) dissolved in 300 com. of ethyl alcohol are shaken with 0.5 g. of platinum oxide in an atmosphere of hydrogen. When 1 mol of hydrogen is taken up, the velocity of hydrogenation drops to about one quarter of the original velocity. The catalyst is filtered off and the solution is crystallized, thereby obtaining about 8 g. of Nor-Lobelanidinechlorhydrate. To the mother liquor there is added ether; after standing awhile a mixture of unchanged Nor- Lobelanine, Nor-Lobelidinechlorhydrate and Nor- Lobelanidine crystallizes out from the mother liquor, which then nearly only contains dissolved the soluble Nor-Lobelidinechlorhydrate, which is precipitated by addition of ether or petrol ether to this new mother liquor. The precipitate, which is smeary, may be purified by crystallization from alcohol ether mixtures, thus obtaining about 10 g. of cristalline Nor-Lobelidinechlorhydrate melting at 201. The intermediate fraction may .furnish 2 g. of the same substance. The Nor-Lobelanidine, obtained as by-product may be oxidized to Nor-Lobelanine, which may be again used for hydrogenation.

The following reactions occur:

, also about 30% unchanged starting material H Hg H H 30% yield 0) o H, I? H; (IJHOH H eHl HOH

Hr- H:

0015-0 o-om f 95 nor-lobelidine orn-orroH-om.

(5) 315 g. '(1 mol) of dry on, a'-diphenacylpyridine are heated with 900 g. of'the methyl ester of p-toluene sulfonic acid for about one hour to temperatures of about 150-160 C. The quaternary salt of the base used already starts to crystallize in the warmth. The reaction mixture is cooled, thoroughly, stirred with dry benzene or ether and then separated by suction. 450g. of a,a-diphenacylpyridinetoluenesulfomethylate are obtained on the filter. The salt crystallizes from methyl alcohol in long needles melting at 228 C. It furnishes the free base by treating its aqueous solution with ammonia.

191 g. of a -diphenacylpyridinetoluenesulfomethylate dissolved or suspended in 2000 ccmlof methyl alcohol are shaken with 2 g. of platinum oxide in an atmosphere of hydrogen. 4'7 liters hydrogen are taken up in about 3 hours when the reaction comes to a standstill. The following reaction takes place:

H H v Hr H2 l V H +5Hg H H 141 ca om-0.11, CH: CH5 \CE:s OH: I so, oHoH 00 won 1) tHr-C Ha According to the invention it ispossible to obtain new hydrogenation products from oc-DYIldYl and .a-piperdylketones, which new products are of great interest for their near relation to the natural Lobelia alkaloids. The invention thus is a valuable ,step' for synthetically making Lobelia alkaloids and similar bodies; thus for example Lobelidine (d-l-Lobeline), Lobelanidine or Nor-Lobelanidine may be prepared from an easily obtainable diketone of the pyridine series.v

We claim:

1. A method consisting in hydrogenating a compound havingfive carbon and one nitrogen atoms, in cyclic unionand at least one side chain con taining a keto group in one of the u-positions, by treating the starting material with hydrogen in the presence of a hydrogenation catalyst and in the presence of an organic solvent, until at least one mol of hydrogen is taken up and at least one keto group is transformed into a secondary alcohol group. 2 A method consisting"in hydrogenating compound from the group consisting of pyridine and its homologues havingat least one side chain containing a ket o group in one of the oc-DOSitlOIlS, by treating the starting material with hydrogen in the presence of a hydrogenation catalylst, until at least one mol of hydrogen is taken upfand at least one keto group .is transformed into a secondary. alcoholgroupf 3. A method consisting in hydrogenating a compound selected from the group consisting of pyridine audits homologueshaving at least one phenacyl group, ino'ne of the :a-positions, by. treating the starting vmaterialwith hydrogen .in the presence of ahydrogenation catalyst, until at least one mol, of hydrogen is Stahenup'and at least one keto group is transformed into, a: secondary alcohol group.

4. A method consisting in group, in one of the tar-positions, -by ,.treating the starting material with hydrogen in the presence of a hydrogenation catalyst and in thepresence of an organic solvent, until at least one mol of hydrogen is taken up andat least one'keto group is transformed into a secondary alcohol group.

5. A method according to claii'nl inwhich after transformation of one keto group into" a secondary alcohol group the further hydrogenation is carried out in stages.

6. A method consisting in treating a quaternary salt of a pyridine compound having at least one phenacyl group in one of the u positions, with hydrogen, in the presence of 'a-hydrogenation catalyst.

'7. A method according to claim 1 in which the hydrogenation is carried outwith hydrogen, in-

.the presence of a hydrogenation catalyst of the platinum group. I

8. A method according to claim 1 in which the hydrogenation is carried out with hydrogen, in the presence of an oxide of ,a metal of the platinumgroup' 9. A method according to claim 1 in which the hydrogenation is carried out with hydrogen, in the presence of a metal ofthe platinum group.

10. A method according to claim 1 in which the hydrogenation is carried outwith hydrogen, in the presence of a metal of the platinum group precipitated on a carrier.

11. A method according to claim 1 in which the hydrogenation is carried outwith hydrogen, in the presence of nickel.

I I hydrogenatin'g piperidine compound with at least one phenacyl.

.12. A-methodior making an oz-PhGIlYlhYdIOXY- ethylpyridine, which consists in treating onphenacylpyridine with hydrogen, in the presence of a hydrogenation catalyst.

.13. A method for making an a-phenylhydroxyethyl piperidine, which consists in treating a-phenacylpyridine with hydrogen, in the presence of a hydrogenation catalyst, until four mols of-hydrogen are taken upv14. A method consisting intreating e u-diphenacylpyridine with hydrogen, in the presence of a hydrogenation catalyst, until one mol of hydrogen is taken up and a-phenylhydroxyethyla -phenacylpyridine is :formed.

15. A method consisting in treating cad-diphenacyl-pyridine with hydrogen, in the presence of a hydrogenation catalyst, until two mols of hydrogen are taken up and a,a-diphe nylhydroxyethylpyridine is formed.

16. A method consisting intreating oc,oc'-dlphenacylpyridine with hydrogen, in the presence of a hydrogenation catalyst, until five mols of hydrogen are taken up and a,ob-diphenylhydroxyethylpiperidine (Nor-Lobelanidine) is formed.

17. A method consistingin treating u,a'-dlphenacylpiperidine with hydrogen, in the presence of a hydrogenation catalyst and in the presence of an organic solvent, until one mol of hydrogen is taken up and a-phenylhydroxyethyl-a-phenacylpiperidine (Nor-Lobelin) is formed.

18. A method consisting in treating zx,a'diphenacylpiperidine with hydrogen, in the presence of a hydrogenation catalyst and in the presence of an organic solvent, until two mols of hydrogen ar'eitaken up .and' a -diphenylhydroxyethylpiperidine (lflor-Lobelanidine) is formed.

19.,A method consisting in treating N-nethylated apt-diphenacylpiperidine in the presence of ahydrogenationgcatalyst and in the presence of an organic solvent with hydrogen, until two mols of hydrogen are taken up and the two keto groups of the side chainsare transformed into secondary alcohol groups whereby N-methylated 0 m-diphenylhydroxyethylpiperidine is formed.

20. A method consisting in treating N-methylated 11,11-diphenacylpiperidine, which is substituted in the methyl group by a hydrocarbon radical, in the presence of a hydrogenation catalyst and in'thefpresence of an organic solvent, with hydrogen, until two mols of hydrogen are taken up and the corresponding N-substituted a,a-diphenylhydroxyethylpiperidine is formed. .21. A method consisting in treating a quaternary saltof a,a-diphenacylpyridine containing an N-methyl group in the presence ofa hydrog'enation catalyst with hydrogen, until four mols of hydrogen are taken up and N-methylated a-phenylhydr'oxyethyl-u'-phenacylpiperidinep is formed. r

22. A method consisting in treating a quarternary salt of a,u'-diphenacylpyridine containing an N-methyl group substituted by a hydrocarbon radical with hydrogen in the presence of a hydrogenation catalyst, until four mols of hydrogen are taken up and an N-methylatedmphenylhydroxyethyl-u-phenacylpiperidine is formed which is substituted in the methyl group by a hydrocarbon radical.

23. A method consisting in treating a quaternary salt or" a,u'-diphenacylpyridine containing an N methyl group in the presence of a hydrogenation catalyst with hydrogen, until five mols of hydrogen are taken up and N-methylated a diphenylhydroxyethylpiperidine is formed.

. 24. A method consisting in treating a quaternary salt of u,a'-diphenacylpyridine containing an N-methyl group substituted by a hydrocarbon radical in the presence of a hydrogenation cata-- lyst with hydrogen, until five mols of hydrogen are taken up and N-methylated a,u'-diphenylhydroxyethylpiperidine is formed which is substituted in the methyl group by a hydrocarbon radical.

25. A method consisting in hydrogenating a piperidine compound with at least one phenacyl group in one of the iii-positions, by treating the starting material with hydrogen in the presence of a hydrogenation catalyst selected from the group consisting of a metal of the platinum group precipitated on a carrier, and nickel, until at least one mol of hydrogen is taken up and at least one keto group is transformed into a secondary alcohol group.

26. A method consisting in treating a, z'-diphenacylpiperidine with hydrogen, in the presence of a hydrogenation catalyst selected from the group consisting of a metal of the platinum group precipitated on. a carrier, and nickel, until one mol of hydrogen is taken up and u-phenylhydroxyethyl-a'-phenacylpiperidine (Nor-Lobeline) is formed.

27. A method consisting in treating a,oz.'-dl phenacylpiperidine with hydrogen, in the presence of a hydrogenation catalyst selected from the group consisting of a metal of the platinum group precipitated on a carrier, and nickel, until two mols of hydrogen are taken up and a,oc'-dlphenylhydroxyethylpiperidine (Nor Lobelanidine) is formed.

28. A method consisting in treating N-methylated c -diphenacy1piperidine in the presence of a hydrogenation catalyst selected from the group consisting of a metal of the platinum group precipitated on a carrier, and nickel, with hydrogen, until two mols of hydrogen are taken up and the two keto groups of the side chains are transformed into secondary alcohol groups whereby N-rnethylated e diphenylhydroxyethylpiperidine is termed.

29. A method consisting in treating N-methylated o e-diphenacylpiperidine, which is substituted in the methyl group by a hydrocarbon radical, in the presence of a hydrogenation catalyst selected from the group consisting of a metal of the platinum group precipitated on a carrier, and nickel, with hydrogen, until two mols of hydrogen are taken up and the corresponding N-substituted o,a' -diphenylhydroxyethylpiperidine is formed.

30. A method consisting in hydrogenating a compound having five carbon and one nitrogen atoms, incyclic union and at least one side chain containing a keto group in one of the a-positions, by treating the starting material with hydrogen in the presence of a hydrogenation catalyst selected from the group consisting of a metal of the platinum group precipitated on a carrier, and nickel, until at least one mol of hydrogen is taken up and at least one keto group is transformed into a secondary alcohol group.

31. A method consisting in hydrogenating a compound having five carbon and one nitrogen atoms, in cyclic union and at least one side chain containing a keto group in one of the iii-positions, by treating the starting material with hydrogen in the presence of a hydrogenation catalyst selected from the group consisting of a metal of the platinum group precipitated on a carrier, and nickel, and in the presence of an organic solvent until at least one mol of hydrogen is taken up and at least one keto group is transformed into a secondary alcohol group.

32. A method consisting in hydrogenating a compound having five carbon and one nitrogen atoms, in cyclic union and at least one side chain containing a keto group in one of the u-positions, by treating the starting material with hydrogen in the presence of a hydrogenation catalyst comprising an oxide of a metal of the platinum group, until at least one mol of hydrogen is taken up and at least one keto group is transformed into a secondary alcohol group.

33. A method consisting in hydrogenating a compound having five carbon and one nitrogen atoms, in cyclic union and at least one side chain containing a keto group in one of the a-positions, by treating the starting material with hydrogen in the presence-of a hydrogenation catalyst comprising a metal of the platinum group precipitated on a. carrier, until at least one keto group is transformed into a secondary alcohol group.

34. A method consisting in hydrogenating a compound having five carbon and one nitrogen atoms, in cyclic union and at least one side chain containing a keto group in one of the Jr-positions, by treating the starting material with hydrogen in the presence of a hydrogenation catalyst comprising nickel until at least one mol of hydrogen is taken up and at least one keto group is transformed into a secondary alcohol group.

35. A method consisting in hydrogenating a compound selected from the group consisting of pyridine and its homologues having at least one side chain containing a keto group in one of the iii-positions, by treating the starting material with hydrogen in the presence of a hydrogenation catalyst and in the presence of an organic solvent, until at least one mol of hydrogen is taken up and at least one keto group is transformed into a secondary alcohol group.

GEORG SCHEUING. LUDWIG WIN'I'ERHALDER. 

